Preparation method of polyfluoro-substituted benzene series compounds based on diazonium salt

Abstract

The invention relates to the technical field of medical intermediate processing, and discloses a preparation method of polyfluoro substituted benzene series compounds based on diazonium salt, which comprises the following steps: 1) taking fluoroaniline substances, fluoboric acid and sodium nitrite as raw materials, reacting for 2-4 hours at the reaction temperature of lower than 10 DEG C, and performing suction filtration and purification to obtain a diazonium salt intermediate; 2) distilling the diazonium salt intermediate at 130-150 DEG C, and decomposing the diazonium salt intermediate to obtain a compound which is o-difluorobenzene, p-difluorobenzene or 1, 2, 4-trifluorobenzene; according to the method, a diazonium salt intermediate is prepared by taking a fluorine-containing aniline substance, fluoboric acid and sodium nitrite as raw materials, the yield of the step can reach 95% or above, the yield of pure o-difluorobenzene obtained by heating and decomposing diazonium salt can reach 80% or above, and the yield of p-difluorobenzene can also reach 85% or above; the yield of the obtained 1, 2, 4-trifluorobenzene can also reach 84% or above; the method is short in process, mild in reaction, simple in operation, high in product yield and simple in purification operation, and the product purity can reach 99% or above.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical intermediate processing, and in particular to a method for preparing a polyfluorinated substituted benzene series compound based on diazonium salt. Background Art

[0002] Aromatic fluorides are a class of organic compounds containing aromatic rings and fluorine atoms. They have important applications in the fields of medicine, pesticides, energy, and electronics. The main structural formula of aromatic fluorides is shown below:

[0003]

[0004] At present, the existing preparation methods of o-difluorobenzene, p-difluorobenzene and 1,2,4-trifluorobenzene at home and abroad mainly include:

[0005] (1) The Balz-Schiemann reaction is the main method for synthesizing o-difluorobenzene, p-difluorobenzene and 1,2,4-trifluorobenzene. The reaction uses aromatic diazonium salts and fluoroboric acid as raw materials to react to produce insoluble diazonium fluoroborates or directly diazotize aromatic amines with sodium pyrophosphate and fluoroboric acid. When heated or exposed to light, it decomposes to release nitrogen and highly toxic boron trifluoride gas, and produces aromatic fluorides.

[0006] Depending on the raw materials used, the process routes for preparing o-difluorobenzene, p-difluorobenzene and 1,2,4-trifluorobenzene can also be: using o-chloronitrobenzene and o-phenylenediamine as raw materials to prepare o-difluorobenzene; using 2,4-difluoroaniline as raw materials to prepare 1,2,4-trifluorobenzene; using p-phenylenediamine as raw materials to prepare p-difluorobenzene, etc.

[0007] The advantages of this synthetic route are stable reaction and good reproducibility. The disadvantages are: the reaction needs to undergo aniline salt formation first, which is a highly exothermic process and cumbersome operation, which is not conducive to industrial production. At the same time, the release of nitrogen and highly toxic boron trifluoride gas requires additional treatment procedures.

[0008] (2) Halogen exchange reaction is to treat o-, m-, and p-dihalobenzenes with metal halides (such as potassium fluoride and silver fluoride) to obtain N2 Nucleophilic substitution reaction, introduction of fluorine groups. Although this method has a short route, it has obvious disadvantages such as large amount of fluorination reagent, high reaction temperature (250-500°C), long reaction time, low selectivity, excessive by-products, and severe loss of product yield during the purification operation.

[0009] In 2001, Zhu Xuedong and others used meta-dichlorobenzene as a raw material to prepare meta-difluorobenzene. First, they introduced the electron-withdrawing nitro group to activate the chlorine atom through a one-step nitration reaction, then used potassium fluoride as a fluorination reagent in DMSO solvent to replace two chlorine atoms to obtain 2,4-difluoronitrobenzene, and finally reduced the nitro group to obtain meta-difluorobenzene. This reaction is a diatomic fluorination reaction. There are many influencing factors during the reaction process, resulting in low product purity and difficulty in separating by-products, so it is not suitable for industrial production.

[0010] (3) In 1998, Paul et al. used a fluorine gas and nitrogen mixed gas with a mass fraction of 10% to carry out a fluorination reaction to prepare o-difluorobenzene, but the yield was only 7%. In 2017, He Jianming et al. disclosed a method for preparing o-difluorobenzene by fluorine gas fluorination reaction (CN107226773). The method uses 2-(trimethylsilyl)phenyl trifluoromethanesulfonate as a raw material, first generates benzyne under the action of potassium fluoride, and then introduces fluorine gas for fluorination reaction to obtain the product o-difluorobenzene. Although this method is a new method for preparing o-difluorobenzene, its raw materials are expensive, the intermediate benzyne is too active, and decomposition has occurred after the reaction is completed and when fluorine gas is introduced, resulting in low product purity and low yield. Therefore, the feasibility of this method is low and it is not suitable for industrial production.

[0011] Xiang Jinglai. Research and development of continuous diazotization process and pilot plant for o-fluoroaniline [D]. Zhejiang University of Technology, 2017. The reaction of primary aromatic amine and nitrous acid to generate diazonium salt is called diazotization reaction. The obtained diazonium salt occupies an extremely important position in organic synthesis, medicine, photosensitive materials, dye industry and carbon material modification. However, the existing diazonium salt reaction mainly uses primary aromatic amine and nitrous acid as raw materials to prepare diazonium salt. The preparation process has the problems of long reaction time, low yield and high energy consumption. This document proposes a solution to this problem from the perspective of the reaction device.

[0012] Another example is the method disclosed in Liu Zhe and Ma Mei. Synthesis of 2,4-difluoroaniline by diazotization and fluorination [J]. Chemical Engineering Management, 2014, (14): 128. Boric acid crystals or powder are added to wastewater hydrogen fluoride at 0°C to obtain fluoroboric acid, m-phenylenediamine is added to hydrochloric acid, the temperature is raised to dissolve, and the temperature is kept constant for 1 hour, and then the prepared fluoroboric acid is added at about -5°C NaNO to obtain a diazonium salt, and the diazonium salt is heated to decompose to obtain m-difluorobenzene, and then m-difluorobenzene is added to a mixed solution of sulfuric acid and nitric acid, stirred for reaction, and dried to obtain 2,4-difluoronitrobenzene, and then iron powder and CaCl solution are mixed and added to the obtained 2,4-difluoronitrobenzene, heated to reflux for 3 hours, and then the distilled mixture is dried and separated to obtain 2,4-difluoroaniline. Although the yield of this method can reach 89%, the reaction process is cumbersome and the reaction path is long, which is not suitable for industrial production.

[0013] Another example is the method disclosed in Zhang Hong. Synthesis and Research of o-difluorobenzene [J]. Organic Fluorine Industry, 2006, (03): 14-16. The o-fluoroaniline is used as a raw material and reacted with a nitrous acid reagent in the presence of hydrochloric acid, sulfuric acid or hydrobromic acid to undergo a diazotization reaction at -20 to 5°C. The resulting reaction solution is filtered and reacted with fluoroboric acid to obtain o-fluorobenzene diazonium fluoroborate. After filtration and drying, the obtained powdered o-fluorobenzene diazonium fluoroborate is mixed with a chlorinated aromatic solvent and distilled under reduced pressure at 140°C to remove water. The fraction obtained is then decomposed at 155°C and distilled to obtain o-difluorobenzene. The actual yield is 78.2%. This method still has the problems of cumbersome operation, long reaction path, and difficulty in preparing diazonium compounds.

[0014] It can be seen from the above description that the above problems are urgently needed to be solved in the prior art. Summary of the invention

[0015] The object of the present invention is to provide a method for preparing a series of polyfluorinated substituted benzene compounds based on diazonium salts, which method does not require the use of hydrochloric acid to form salts with a raw material fluorinated substituted aniline, simplifies the operation steps, has milder reaction conditions, is simpler to operate, and has excellent yield.

[0016] The scheme of the present invention is:

[0017] A method for preparing a series of polyfluorinated substituted benzene compounds based on diazonium salts comprises the following steps:

[0018] 1) Using fluoroaniline, fluoroboric acid and sodium nitrite as raw materials, reacting at a temperature below 10°C for 2 to 4 hours, and then filtering and purifying to obtain a diazonium salt intermediate;

[0019] 2) distilling the diazonium salt intermediate at 130-150° C., and obtaining a compound after decomposition of the diazonium salt intermediate, wherein the compound is o-difluorobenzene, p-difluorobenzene or 1,2,4-trifluorobenzene.

[0020] As a preferred technical solution, the fluoroaniline substance used in the preparation of o-difluorobenzene is o-fluoroaniline.

[0021] As a preferred technical solution, the fluoroaniline substance used in the preparation of p-difluorobenzene is p-fluoroaniline.

[0022] As a preferred technical solution, the fluoroaniline substance used in the preparation of 1,2,4-trifluorobenzene is 2,4-difluoroaniline.

[0023] As a preferred technical solution, in the step 1), the fluoroaniline substance is first cooled to 4-6°C before the reaction, and then fluoroboric acid is slowly added dropwise, and the temperature of the resulting mixture is kept below 10°C and stirred for 0.5h; then sodium nitrite is slowly added dropwise and the temperature of the mixture is kept below 10°C.

[0024] As a preferred technical solution, the operation of filtration and purification in step 1) is to filter the reaction liquid to obtain a filter cake, wash the filter cake with anhydrous ethanol 1 to 2 times, and then vacuum dry the filter cake at 50°C to obtain the diazonium salt intermediate.

[0025] As a preferred technical solution, when the diazonium salt intermediate is distilled in step 2), the boron trifluoride gas generated by the distillation is pumped away by a vacuum water pump to avoid environmental pollution.

[0026] As a preferred technical solution, the fluoroboric acid is a fluoroboric acid aqueous solution with a mass concentration of 40%.

[0027] As a preferred technical solution, the sodium nitrite is a sodium nitrite solution, and the sodium nitrite solution is a mixture of NaNO2 and H2O, the NaNO2 is 0.54-5.40 mol, and the H2O is 100-700 mL.

[0028] As a preferred technical solution, in the step 1), the molar ratio of fluoroaniline substances, fluoroboric acid and sodium nitrite is 1:2:0.5-1.2.

[0029] Advantages of the present invention:

[0030] The method does not need to use hydrochloric acid to form salt with the raw material fluorine-substituted aniline, simplifies the operation steps, has milder reaction conditions, simpler operation and excellent yield.

[0031] 1) The present invention provides a method for preparing a series of polyfluorosubstituted benzene compounds based on diazonium salts. The method uses fluoroaniline substances, fluoroboric acid and sodium nitrite as raw materials to prepare a diazonium salt intermediate. The yield of this step can reach more than 95%. After that, the yield of pure o-difluorobenzene obtained by heating and decomposing the diazonium salt can reach more than 80%, and the yield of the obtained p-difluorobenzene can also reach more than 85%; the yield of the obtained 1,2,4-trifluorobenzene can also reach more than 84%. The method has a short process, mild reaction, simple operation, high product yield, simple purification operation, and the purity of the obtained product can reach more than 99%.

[0032] 2) The method for preparing a series of polyfluorosubstituted benzene compounds based on diazonium salts provided in the present application can be used to produce o-difluorobenzene, p-difluorobenzene, and 1,2,4-trifluorobenzene, which is conducive to industrial application. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is a gas chromatogram of o-difluorobenzene, the product prepared in Example 1 of the present application;

[0034] Figure 2 This is the gas chromatogram of the product p-difluorobenzene prepared in Example 7 of the present application;

[0035] Figure 3This is the gas chromatogram of the product 1,2,4-trifluorobenzene prepared in Example 12 of the present application. DETAILED DESCRIPTION

[0036] In order to make the technical means, creative features, objectives and effects achieved by the present invention easy to understand, the present invention is further described below in conjunction with specific embodiments.

[0037] The following examples are only used to further illustrate the present invention in detail, but do not constitute any limitation to the present invention; the materials used in the following examples, unless otherwise specified, were purchased from conventional chemical reagent companies and raw material suppliers.

[0038] Example 1: Preparation of o-difluorobenzene

[0039] Weigh o-fluoroaniline (50.0g, 0.45mol) in a 500mL three-necked flask, cool to 5°C in an ice-water bath, slowly drip 143mL (0.90mol) of 40% fluoroboric acid (HBF4) aqueous solution, control the dripping speed, and keep the reaction liquid temperature below 8°C. After the dripping, keep warm and stir for 0.5 hours, then slowly drip 100mL of sodium nitrite solution (NaNO2: 37.3g, 0.54mol; H2O: 100mL), control the dripping speed of the sodium nitrite solution, and keep the reaction liquid temperature below 10°C. After keeping warm and stirring for 2 hours, stop the reaction. Filter by suction, wash the filter cake with anhydrous ethanol 1-2 times, collect the filter cake and dry it at 50°C under vacuum to obtain 75.6g of diazonium salt intermediate with a yield of 80.0%.

[0040] Take the above diazonium salt intermediate (75.6g, 0.36mol), add it to a 1000mL single-necked bottle in batches, set up a distillation apparatus, and use low-temperature cold hydrazine to connect the condenser and the receiving bottle, slowly increase the oil bath temperature to 140°C, the diazonium salt begins to slowly decompose, control the stirring speed and use a vacuum water pump to continuously remove the generated boron trifluoride gas. After the diazonium salt is decomposed, remove the distillation apparatus, and 30.5 grams of pure o-difluorobenzene is obtained in the receiving bottle, with a yield of 74.2%. The gas chromatogram of the obtained product is as follows Figure 1 As shown. Figure 1 It can be seen that the product has high purity and a single peak.

[0041] Example 2: Preparation of o-difluorobenzene

[0042] Weigh o-fluoroaniline (100.0g, 0.9mol) in a 1000mL three-necked flask, cool to 5°C in an ice-water bath, slowly drip 318mL (2.0mol) of 40% fluoroboric acid (HBF4) aqueous solution, control the dripping speed, and keep the temperature of the reaction liquid below 10°C. After the dripping is completed, keep warm and stir for 0.5 hours, then slowly drip 200mL of sodium nitrite solution (NaNO2: 74.5g, 1.08mol; H2O: 200mL), control the dripping speed of the sodium nitrite solution, and keep the temperature of the reaction liquid below 10°C. After the dripping is completed, keep warm and stir for 3 hours to stop the reaction. Filter by suction, wash the filter cake with anhydrous ethanol 1-2 times, collect the filter cake and dry it at 50°C in vacuum to obtain 143.8 grams of diazonium salt intermediate, with a yield of 76.1%.

[0043] Take the above diazonium salt intermediate (143.8g, 0.685mol), add it to a 1000mL single-necked bottle in batches, set up a distillation apparatus, and use low-temperature cold hydrazine to connect the condenser and the receiving bottle, slowly increase the oil bath temperature to 140°C, the diazonium salt begins to slowly decompose, control the stirring speed and use a vacuum water pump to continuously remove the generated boron trifluoride gas. After the diazonium salt is decomposed, remove the distillation apparatus, and obtain 57.6 grams of pure o-difluorobenzene in the receiving bottle, with a yield of 73.7%.

[0044] Example 3: Preparation of o-difluorobenzene

[0045] Weigh o-fluoroaniline (50.0g, 0.45mol) in a 500mL three-necked flask, cool to 5°C in an ice-water bath, slowly drip 12mL (0.8mol) of 40% fluoroboric acid (HBF4) aqueous solution, control the dripping speed, and keep the reaction liquid temperature below 10°C. After the dripping is completed, keep warm and stir for 0.5 hours, then slowly drip 100mL of sodium nitrite solution (NaNO2: 37.3g, 0.54mol; H2O: 100mL), control the dripping speed of the sodium nitrite solution, and keep the reaction liquid temperature below 10°C. After the dripping is completed, keep warm and stir for 4 hours to stop the reaction. Filter by suction, wash the filter cake with anhydrous ethanol 1-2 times, collect the filter cake and dry it at 50°C in vacuum to obtain 89.8g of diazonium salt intermediate with a yield of 95.0%.

[0046] Take the above diazonium salt intermediate (63.8g, 0.304mol), add it to a 1000mL single-necked bottle in batches, set up a distillation apparatus, and use low-temperature cold hydrazine to connect the condenser and the receiving bottle, slowly increase the oil bath temperature to 140°C, the diazonium salt begins to slowly decompose, control the stirring speed and use a vacuum water pump to continuously remove the generated boron trifluoride gas. After the diazonium salt is decomposed, remove the distillation apparatus, and obtain 26.8 grams of pure o-difluorobenzene in the receiving bottle, with a yield of 77.4%.

[0047] Example 4: Preparation of o-difluorobenzene

[0048] Weigh o-fluoroaniline (50.0g, 0.4mol) in a 50mL three-necked flask, cool to 5°C in an ice-water bath, slowly drip 143mL (0.9mol) of 40% fluoroboric acid (HBF4) aqueous solution, control the dripping speed, and keep the reaction liquid temperature below 10°C. After the dripping is completed, keep warm and stir for 0.5 hours, then slowly drip 100mL of sodium nitrite solution (NaNO2: 37.3g, 0.54mol; H2O: 100mL), control the dripping speed of the sodium nitrite solution, and keep the reaction liquid temperature below 10°C. After the dripping is completed, keep warm and stir for 4 hours to stop the reaction. Filter by suction, wash the filter cake with anhydrous ethanol 1-2 times, collect the filter cake and dry it at 50°C in vacuum to obtain 78.9g of diazonium salt intermediate with a yield of 83.5%.

[0049] Take the above diazonium salt intermediate (78.9g, 0.376mol), add it to a 1000mL single-necked bottle in batches, set up a distillation apparatus, and use low-temperature cold hydrazine to connect the condenser and the receiving bottle, slowly increase the oil bath temperature to 140°C, the diazonium salt begins to slowly decompose, control the stirring speed and use a vacuum water pump to continuously remove the generated boron trifluoride gas. After the diazonium salt is decomposed, remove the distillation apparatus, and obtain 33.4 grams of pure o-difluorobenzene in the receiving bottle, with a yield of 78.0%.

[0050] Example 5: Preparation of o-difluorobenzene

[0051] Weigh o-fluoroaniline (50.0g, 0.45mol) in a 500mL three-necked flask, cool to 5°C in an ice-water bath, slowly drip 215mL (1.35mol) of 40% fluoroboric acid (HBF4) aqueous solution, control the dripping speed, and keep the temperature of the reaction liquid below 10°C. After the dripping is completed, keep warm and stir for 0.5 hours, then slowly drip 100mL of sodium nitrite solution (NaNO2: 37.3g, 0.54mol; H2O: 100mL), control the dripping speed of the sodium nitrite solution, and keep the temperature of the reaction liquid below 10°C. After the dripping is completed, keep warm and stir for 2 hours to stop the reaction. Filter by suction, wash the filter cake with anhydrous ethanol 1-2 times, collect the filter cake and dry it at 50°C in vacuum to obtain 83.4 grams of diazonium salt intermediate, with a yield of 88.2%.

[0052] Take the above diazonium salt intermediate (74.5g, 0.355mol), add it to a 1000mL single-necked bottle in batches, set up a distillation apparatus, and use low-temperature cold hydrazine to connect the condenser and the receiving bottle, slowly increase the oil bath temperature to 140°C, the diazonium salt begins to slowly decompose, control the stirring speed and use a vacuum water pump to continuously remove the generated boron trifluoride gas. After the diazonium salt is decomposed, remove the distillation apparatus, and obtain 33.7 grams of pure o-difluorobenzene in the receiving bottle, with a yield of 83.3%.

[0053] Example 6: Preparation of o-difluorobenzene

[0054] Weigh o-fluoroaniline (50.0g, 0.45mol) in a 500mL three-necked flask, cool to 5°C in an ice-water bath, slowly drip 215mL (1.35mol) of 40% fluoroboric acid (HBF4) aqueous solution, control the dripping speed, and keep the reaction liquid temperature below 10°C. After the dripping is completed, keep warm and stir for 0.5 hours, then slowly drip 150mL of sodium nitrite solution (NaNO2: 46.6g, 0.68mol; H2O: 150mL), control the dripping speed of the sodium nitrite solution, and keep the reaction liquid temperature below 10°C. After the dripping is completed, keep warm and stir for 3 hours to stop the reaction. Filter by suction, wash the filter cake with anhydrous ethanol 1-2 times, collect the filter cake and dry it at 50°C in vacuum to obtain 72.7g of diazonium salt intermediate with a yield of 77.0%.

[0055] Take the above diazonium salt intermediate (72.7g, 0.346mol), add it to a 1000mL single-necked bottle in batches, set up a distillation apparatus, and use low-temperature cold hydrazine to connect the condenser and the receiving bottle, slowly increase the oil bath temperature to 140°C, the diazonium salt begins to slowly decompose, control the stirring speed and use a vacuum water pump to continuously remove the generated boron trifluoride gas. After the diazonium salt is decomposed, remove the distillation apparatus, and obtain 31.8 grams of pure o-difluorobenzene in the receiving bottle, with a yield of 80.6%.

[0056] Example 7: Preparation of p-difluorobenzene

[0057] Weigh p-fluoroaniline (50.0g, 0.4mol) in a 500mL three-necked flask, cool to 5°C in an ice-water bath, slowly drip 143mL (0.9mol) of 40% fluoroboric acid (HBF4) aqueous solution, control the dripping speed, and keep the temperature of the reaction liquid below 10°C. After the dripping is completed, keep warm and stir for 0.5 hours, then slowly drip 100mL of sodium nitrite solution (NaNO2: 37.3g, 0.54mol; H2O: 100mL), control the dripping speed of the sodium nitrite solution, and keep the temperature of the reaction liquid below 10°C. After the dripping is completed, keep warm and stir for 3 hours to stop the reaction. Filter by suction, wash the filter cake with anhydrous ethanol 1-2 times, collect the filter cake and dry it at 50°C in vacuum to obtain 81.9g of diazonium salt intermediate, with a yield of 86.6%.

[0058] Take the above diazonium salt intermediate (68.4g, 0.326mol), add it to a 1000mL single-necked bottle in batches, set up a distillation apparatus, and use low-temperature cold hydrazine to connect the condenser and the receiving bottle, slowly increase the oil bath temperature to 140°C, the diazonium salt begins to slowly decompose, control the stirring speed and use a vacuum water pump to continuously remove the generated boron trifluoride gas. After the diazonium salt is decomposed, remove the distillation apparatus, and obtain 27.7 grams of pure p-difluorobenzene in the receiving bottle, with a yield of 74.6%. The gas chromatogram of the obtained product p-fluoroaniline is as follows Figure 2 As shown. Figure 2 It can be seen that the product has high purity and a single peak.

[0059] Example 8: Preparation of p-difluorobenzene

[0060] Weigh p-fluoroaniline (50.0g, 0.45mol) in a 500mL three-necked flask, cool to 5°C in an ice-water bath, slowly drip 143mL (0.9mol) of 40% fluoroboric acid (HBF4) aqueous solution, control the dripping speed, and keep the reaction liquid temperature below 10°C. After the dripping is completed, keep warm and stir for 0.5 hours, then slowly drip 150mL of sodium nitrite solution (NaNO2: 55.9g, 0.81mol; H2O: 150mL), control the dripping speed of the sodium nitrite solution, and keep the reaction liquid temperature below 10°C. After the dripping is completed, keep warm and stir for 2-4 hours to stop the reaction. Filter by suction, wash the filter cake with anhydrous ethanol 1-2 times, collect the filter cake and dry it at 50°C in vacuum to obtain 70.9g of diazonium salt intermediate with a yield of 75.1%.

[0061] Take the above diazonium salt intermediate (70.9g, 0.338mol), add it to a 1000mL single-necked bottle in batches, set up a distillation apparatus, and use low-temperature cold hydrazine to connect the condenser and the receiving bottle, slowly increase the oil bath temperature to 140°C, the diazonium salt begins to slowly decompose, control the stirring speed and use a vacuum water pump to continuously remove the generated boron trifluoride gas. After the diazonium salt is decomposed, remove the distillation apparatus, and obtain 31.6 grams of pure p-difluorobenzene in the receiving bottle, with a yield of 82.1%.

[0062] Example 9: Preparation of p-difluorobenzene

[0063] Weigh p-fluoroaniline (50.0g, 0.45mol) in a 500mL three-necked flask, cool to 5°C in an ice-water bath, slowly drip 200mL (1.26mol) of 40% fluoroboric acid (HBF4) aqueous solution, control the dripping speed, and keep the reaction liquid temperature below 10°C. After the dripping is completed, keep warm and stir for 0.5 hours, then slowly drip 100mL of sodium nitrite solution (NaNO2: 46.6g, 0.675mol; H2O: 100mL), control the dripping speed of the sodium nitrite solution, and keep the reaction liquid temperature below 10°C. After the dripping is completed, keep warm and stir for 4 hours to stop the reaction. Filter by suction, wash the filter cake with anhydrous ethanol 1-2 times, collect the filter cake and dry it at 50°C in vacuum to obtain 79.1g of diazonium salt intermediate with a yield of 83.7%.

[0064] Take the above diazonium salt intermediate (79.1g, 0.377mol), add it to a 1000mL single-necked bottle in batches, set up a distillation apparatus, and use low-temperature cold hydrazine to connect the condenser and the receiving bottle, slowly increase the oil bath temperature to 140°C, the diazonium salt begins to slowly decompose, control the stirring speed and use a vacuum water pump to continuously remove the generated boron trifluoride gas. After the diazonium salt is decomposed, remove the distillation apparatus, and obtain 36.2 grams of pure p-difluorobenzene in the receiving bottle, with a yield of 84.3%.

[0065] Example 10: Preparation of p-difluorobenzene

[0066] Weigh p-fluoroaniline (200.0g, 1.80mol) in a 2000mL three-necked flask, cool to 5°C in an ice-water bath, slowly drip 714mL (4.5mol) of 40% fluoroboric acid (HBF4) aqueous solution, control the dripping speed, and keep the reaction liquid temperature below 10°C. After the dripping is completed, keep warm and stir for 0.5 hours, then slowly drip 350mL of sodium nitrite solution (NaNO2: 149.0g, 2.16mol; H2O: 350mL), control the dripping speed of the sodium nitrite solution, and keep the reaction liquid temperature below 10°C. After the dripping is completed, keep warm and stir for 2 hours to stop the reaction. Filter by suction, wash the filter cake with anhydrous ethanol 1-2 times, collect the filter cake and dry it at 50°C in vacuum to obtain 310.5g of diazonium salt intermediate, with a yield of 82.2%.

[0067] Take the above diazonium salt intermediate (310.5g, 1.479mol), add it to a 2000mL single-necked bottle in batches, set up a distillation apparatus, and use low-temperature cold hydrazine to connect the condenser and the receiving bottle, slowly increase the oil bath temperature to 140°C, the diazonium salt begins to slowly decompose, control the stirring speed and use a vacuum water pump to continuously remove the generated boron trifluoride gas. After the diazonium salt is decomposed, remove the distillation apparatus, and obtain 133.7 grams of pure p-difluorobenzene in the receiving bottle, with a yield of 79.3%.

[0068] Example 11: Preparation of p-difluorobenzene

[0069] Weigh p-fluoroaniline (500.0g, 4.50mol) in a 5000mL three-necked flask, cool to 5°C in an ice-water bath, slowly drip 1428mL (9.0mol) of 40% fluoroboric acid (HBF4) aqueous solution, control the dripping speed, and keep the reaction liquid temperature below 10°C. After the dripping is completed, keep warm and stir for 0.5 hours, then slowly drip 700mL of sodium nitrite solution (NaNO2: 372.6g, 5.4mol; H2O: 700mL), control the dripping speed of the sodium nitrite solution, and keep the reaction liquid temperature below 10°C. After the dripping is completed, keep warm and stir for 3 hours to stop the reaction. Filter by suction, wash the filter cake with anhydrous ethanol 1-2 times, collect the filter cake and dry it at 50°C in vacuum to obtain 815.9 grams of diazonium salt intermediate, with a yield of 86.4%.

[0070] Take the above diazonium salt intermediate (815.9g, 3.887mol), add it to a 2000mL single-necked bottle in batches, set up a distillation apparatus, and use low-temperature cold hydrazine to connect the condenser and the receiving bottle, slowly increase the oil bath temperature to 140°C, the diazonium salt begins to slowly decompose, control the stirring speed and use a vacuum water pump to continuously remove the generated boron trifluoride gas. After the diazonium salt is decomposed, remove the distillation apparatus, and obtain 378.4 grams of pure p-difluorobenzene in the receiving bottle, with a yield of 85.4%.

[0071] Example 12: Preparation of 1,2,4-trifluorobenzene

[0072] Weigh 2,4-difluoroaniline (50.0g, 0.39mol) in a 500mL three-necked flask, cool to 5°C in an ice-water bath, slowly drip 124mL (0.78mol) of 40% fluoroboric acid (HBF4) aqueous solution, control the dripping speed, and keep the reaction liquid temperature below 10°C. After the dripping, keep warm and stir for 0.5 hours, then slowly drip 100mL of sodium nitrite solution (NaNO2: 40.4g, 0.59mol; H2O: 100mL), control the dripping speed of the sodium nitrite solution, and keep the reaction liquid temperature below 10°C. After the dripping, keep warm and stir for 2 hours to stop the reaction. Filter by suction, wash the filter cake with anhydrous ethanol 1-2 times, collect the filter cake and dry it at 50°C in vacuum to obtain 66.2g of diazonium salt intermediate with a yield of 74.9%.

[0073] Take the above diazonium salt intermediate (66.2g, 0.29mol), add it to a 1000mL single-necked bottle in batches, set up the distillation device, and use low-temperature cold hydrazine to connect the condenser and the receiving bottle, slowly increase the oil bath temperature to 140°C, the diazonium salt begins to slowly decompose, control the stirring speed and use a vacuum water pump to continuously remove the generated boron trifluoride gas. After the diazonium salt is decomposed, remove the distillation device, and 27.6 grams of pure 1,2,4-trifluorobenzene is obtained in the receiving bottle, with a yield of 72.0%. The chromatogram of the obtained product is as follows Figure 3 As shown by Figure 3 It can be seen that the product has high purity and a single peak.

[0074] Example 13: Preparation of 1,2,4-trifluorobenzene

[0075] Weigh 2,4-difluoroaniline (100.0g, 0.775mol) in a 1000mL three-necked flask, cool to 5°C in an ice-water bath, slowly drip 272mL (1.71mol) of 40% fluoroboric acid (HBF4) aqueous solution, control the dripping speed, and keep the temperature of the reaction liquid below 10°C. After the dripping, keep warm and stir for 0.5 hours, then slowly drip 200mL of sodium nitrite solution (NaNO2: 96.3g, 1.40mol; H2O: 200mL), control the dripping speed of the sodium nitrite solution, and keep the temperature of the reaction liquid below 10°C. After the dripping, keep warm and stir for 4 hours to stop the reaction. Filter by suction, wash the filter cake with anhydrous ethanol 1-2 times, collect the filter cake and dry it at 50°C in vacuum to obtain 131.5g of diazonium salt intermediate with a yield of 74.4%.

[0076] Take the above diazonium salt intermediate (131.5g, 0.577mol), add it to a 2000mL single-necked bottle in batches, set up a distillation device, and use low-temperature cold hydrazine to connect the condenser and the receiving bottle, slowly increase the oil bath temperature to 150°C, the diazonium salt begins to slowly decompose, control the stirring speed and use a vacuum water pump to continuously remove the generated boron trifluoride gas. After the diazonium salt is decomposed, remove the distillation device, and obtain 64.5 grams of pure 1,2,4-trifluorobenzene in the receiving bottle, with a yield of 84.7%.

[0077] Example 14: Preparation of 1,2,4-trifluorobenzene

[0078] Weigh 2,4-difluoroaniline (100.0g, 0.775mol) in a 1500mL three-necked flask, cool to 5°C in an ice-water bath, slowly drip 431mL (2.71mol) of 40% fluoroboric acid (HBF4) aqueous solution, control the dripping speed, and keep the reaction liquid temperature below 10°C. After the dripping, keep warm and stir for 0.5 hours, then slowly drip 200mL of sodium nitrite solution (NaNO2: 107.0g, 1.55mol; H2O: 200mL), control the dripping speed of the sodium nitrite solution, and keep the reaction liquid temperature below 10°C. After the dripping, keep warm and stir for 3 hours to stop the reaction. Filter by suction, wash the filter cake with anhydrous ethanol 1-2 times, collect the filter cake and dry it at 50°C in vacuum to obtain 140.5g of diazonium salt intermediate with a yield of 79.5%.

[0079] Take the above diazonium salt intermediate (140.5g, 0.616mol), add it to a 2000mL single-necked bottle in batches, set up a distillation device, and use low-temperature cold hydrazine to connect the condenser and the receiving bottle, slowly increase the oil bath temperature to 140°C, the diazonium salt begins to slowly decompose, control the stirring speed and use a vacuum water pump to continuously remove the generated boron trifluoride gas. After the diazonium salt is decomposed, remove the distillation device, and obtain 67.9 grams of pure 1,2,4-trifluorobenzene in the receiving bottle, with a yield of 83.5%.

[0080] Embodiment 15

[0081] The difference from Example 1 is that: after the fluoroaniline substance is cooled to 4°C, 40% fluoroboric acid is slowly dripped in; the molar ratio of the fluoroaniline substance, fluoroboric acid, and sodium nitrite is 1:2:0.5. The diazonium salt intermediate distillation temperature is 130°C. After the diazonium salt is completely decomposed, the distillation device is removed, and 28.3 grams of pure o-difluorobenzene is obtained in the receiving bottle, with a yield of 68.9%.

[0082] Example 16

[0083] The difference from Example 1 is that: after the fluoroaniline substance is cooled to 6°C, 40% fluoroboric acid is slowly dripped in; the molar ratio of the fluoroaniline substance, fluoroboric acid, and sodium nitrite is 1:2:1.2. The diazonium salt intermediate distillation temperature is 150°C. After the diazonium salt is completely decomposed, the distillation device is removed, and 29.7 grams of pure o-difluorobenzene is obtained in the receiving bottle, with a yield of 72.3%.

[0084] The above shows and describes the basic principles, main features and advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for preparing a series of polyfluorinated substituted benzene compounds based on diazonium salts, characterized in that: The following steps are involved: 1) Using fluoroaniline, fluoroboric acid and sodium nitrite as raw materials, the reaction temperature is below 10 ℃ After reacting for 2 to 4 hours, filtration and purification are performed to obtain the diazonium salt intermediate; 2) distilling the diazonium salt intermediate at 130-150° C., and obtaining a compound after decomposition of the diazonium salt intermediate, wherein the compound is o-difluorobenzene, p-difluorobenzene or 1,2,4-trifluorobenzene.

2. A method for preparing a series of polyfluorosubstituted benzene compounds based on diazonium salts as claimed in claim 1, characterized in that: The fluoroaniline substance used in the preparation of o-difluorobenzene is o-fluoroaniline.

3. A method for preparing a series of polyfluorosubstituted benzene compounds based on diazonium salts as claimed in claim 1, characterized in that: The fluoroaniline substance used in the preparation of p-difluorobenzene is p-fluoroaniline.

4. A method for preparing a series of polyfluorosubstituted benzene compounds based on diazonium salts as claimed in claim 1, characterized in that: The fluoroaniline substance used in the preparation of 1,2,4-trifluorobenzene is 2,4-difluoroaniline.

5. The method for preparing a series of polyfluorosubstituted benzene compounds based on diazonium salts according to claim 1, characterized in that: In the step 1), before the reaction, the fluoroaniline substance is cooled to 4-6°C, and then fluoroboric acid is slowly added dropwise, and the temperature of the resulting mixture is kept below 10°C and stirred for 0.5h; sodium nitrite is then slowly added dropwise and the temperature of the mixture is kept below 10°C.

6. A method for preparing a series of polyfluorosubstituted benzene compounds based on diazonium salts as claimed in claim 1, characterized in that: The operation of the suction filtration purification in the step 1) is to obtain a filter cake by suction filtration of the reaction solution, wash the filter cake with anhydrous ethanol for 1 to 2 times, and then vacuum dry the filter cake at 50° C. to obtain the diazonium salt intermediate.

7. A method for preparing a series of polyfluorosubstituted benzene compounds based on diazonium salts as claimed in claim 1, characterized in that: When the diazonium salt intermediate is distilled in step 2), the boron trifluoride gas generated by the distillation is pumped away by a vacuum water pump.

8. A method for preparing a series of polyfluoro-substituted benzene compounds based on diazonium salts as claimed in claim 1 or 5, characterized in that: The fluoroboric acid is a fluoroboric acid aqueous solution with a mass concentration of 40%.

9. A method for preparing a series of polyfluoro-substituted benzene compounds based on diazonium salts as claimed in claim 1 or 5, characterized in that: The sodium nitrite is a sodium nitrite solution, which is a mixture of NaNO2 and H2O, wherein the NaNO2 is 0.54-5.40 mol, and the H2O is 100-700 mL.

10. The method for preparing a series of polyfluoro-substituted benzene compounds based on diazonium salts according to claim 1, characterized in that: In the step 1), the molar ratio of fluoroaniline substances, fluoroboric acid and sodium nitrite is 1:2:0.5-1.2.

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